Efficient Synthesis of Dihydrobenzofurans
via a Multicomponent Coupling of Salicylaldehydes, Amines, and Alkynes

Rene-Viet Nguyen; Chao-Jun Li

doi:10.1055/s-2008-1078573

LETTER

Efficient Synthesis of Dihydrobenzofurans via a Multicomponent Coupling of Salicylaldehydes, Amines, and Alkynes

Rene-Viet Nguyen, Chao-Jun Li*
Department of Chemistry, McGill University, 801 Sherbrooke St. West, Montreal, QC, H3A 2K6, Canada
Fax: +1(514)3983797; e-Mail: cj.li@mcgill.ca;

Abstract

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Abstract

A simple and efficient synthesis of dihydrobenzofurans was developed using a multicomponent coupling of various salicylaldehydes, amines, and alkynes. The use of aliphatic alkynes containing a heteroatom is critical to the success of the reaction.

Key words

multicomponent coupling - C-H bond reactions - tandem reactions - heterocycles - catalysis

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Referenzen

References and Notes

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Typical Experimental Procedure for the Cu-Catalyzed Coupling of Aldehyde, Amine, and Alkyne under Microwave Irradiation In a 5 mL Biotage microwave vial, salicylaldehyde (209 µL, 2 mmol), morpholine (348 µL, 4 mmol), 2-methyl-3-butyn-2-ol (387 µL, 4 mmol), and CuI (19 mg, 0.10 mmol) were mixed. The vial was then capped and was subjected to microwave irradiation for 30 min at 130 ˚C. The crude mixture was directly isolated via column chromatography on SiO₂ (gradient eluent: hexane-EtOAc = 10:1 to 1:1) to give 241 mg (44% yield) of product (Table [²] , entry 6).

Typical Experimental Procedure for the Ag-Catalyzed Coupling of Aldehyde, Amine, and Alkyne under Normal Heating Conditions Salicylaldehyde (209 µL, 2 mmol), morpholine (348 µL, 4 mmol), 2-methyl-3-butyn-2-ol (387 µL, 4 mmol), and AgCl (14.3 mg, 0.10 mmol) were mixed in a reaction flask at 80 ˚C in a oil bath in MeCN overnight. The solvent was removed under reduced pressure, and the crude mixture was isolated via column chromatography on SiO₂ (gradient eluent: hexane-EtOAc = 10:1 to 1:1) to give 220 mg (44% yield) of product (Table [²] , entry 6).

2-Methyl-1-(3-piperidin-1-yl-3 H -benzofuran-2-ylidene)propan-2-ol (Table 2, Entry 1)
IR (neat): 3419 (br), 2933, 1696, 1463, 1158 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 7.36 (m, 1 H), 7.24 (m, 1 H), 6.99 (m, 1 H) 5.13 (s, 1 H), 4.79 (s, 1 H), 2.58 (m, 2 H), 2.40 (m, 2 H), 1.53-1.39 (m, 12 H) ppm. ^¹³C NMR (75 MHz, CDCl₃): δ = 157.7, 152.2, 129.5, 126.3, 125.4, 122.2, 113.8, 109.9, 70.6, 67.8, 49.6, 30.9, 30.8, 26.5, 24.6 ppm. MS (EI): m/z (%) = 223 [M⁺], 214, 189. HRMS: m/z calcd for C₁₇H₂₃O₂N: 273.1729; found: 273.17.
1-(3-Piperidin-1-yl-3 H -benzofuran-2-ylidenemethyl)-cyclohexanol (Table 2, Entry 2)
IR (neat): 3419 (br), 2948, 1698, 1612, 1464, 1289 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 7.33 (m, 1 H), 7.17 (m, 1 H), 6.91 (m, 1 H), 6.85 (m, 1 H), 5.08 (s, 1 H), 4.74 (s, 1 H), 2.53 (m, 2 H), 2.32 (m, 2 H), 1.85-1.36 (m, 16 H) ppm. ^¹³C NMR (100 MHz, CDCl₃): δ = 157.6, 152.9, 129.4, 126.2, 125.2, 122.1, 112.4, 109.9, 71.7, 67.8, 49.6, 30.0, 26.5, 25.8, 24.6, 23.0 ppm. MS (EI): m/z (%) = 313 [M⁺], 229, 214. HRMS: m/z calcd for C₂₀H₂₇O₂N: 313.2036; found: 313.2042.
N -[1-Ethyl-1-(3-piperidin-1-yl-3 H -benzofuran-2-ylidenemethyl)propyl]-4-methylbenzenesulfonamide (Table 2, Entry 3)
IR (neat): 2970, 2802, 1696, 1612, 1594, 1461, 1157, 1094 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 7.64 (m, 2 H), 7.25 (m, 2 H), 6.92 (m, 2 H), 6.92 (m, 4 H), 5.26 (s, 1 H), 4.53 (s, 1 H), 4.19 (s, 1 H), 2.39 (m, 1 H), 2.27 (m, 1 H), 2.19 (s, 3 H), 2.03 (m, 3 H), 1.74 (m, 3 H), 1.34 (m, 6 H), 0.84 (m, 6 H) ppm. ^¹³C NMR (75 MHz, CDCl₃): δ = 157.5, 153.6, 142.5, 139.9, 129.6, 129.0, 127.4, 126.0, 125.3, 122.2, 110.0, 108.0, 67.8, 62.7, 49.6, 30.3, 26.3, 24.5, 21.6, 8.4 ppm. MS (EI): m/z (%) = 454 [M⁺], 283, 214, 155. HRMS: m/z calcd for C₂₆H₃₄O₃N₂S: 454.2290; found: 454.2282.
4-(3-Piperidin-1-yl-3 H -benzofuran-2-ylidene)butan-2-ol (Table 2, Entry 4)
IR (neat): 3382 (br), 2931, 1701, 1612, 1475, 1218, 1151 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 7.36 (m, 1 H), 7.20 (m, 1 H), 6.94 (m, 1 H), 6.80 (m, 1 H), 4.96 (m, 1 H), 4.78 (s, 1 H), 3.93 (sept, 1 H, J = 6.0 Hz), 2.39 (m, 6 H), 1.53-1.38 (m, 9 H) ppm. ^¹³C NMR (75 MHz, CDCl₃): δ = 158.1, 154.9, 129.5, 126.4, 125.9, 121.7, 109.8, 101.7, 68.1, 67.2, 49.6, 35.4, 26.4, 24.6, 23.1 ppm. MS (EI): m/z (%) = 273 [M⁺], 214, 188. HRMS: m/z calcd for C₁₇H₂₃O₂N: 273.1729; found: 273.1723.
5-(3-Diethylamino-3 H -benzofuran-2-ylidene)pentan-1-ol (Table 2, Entry 5)
IR (neat): 3412 (br), 2935, 1711, 1611, 1463, 1234 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 7.27 (m, 1 H), 7.11 (m, 1 H), 6.84 (m, 1 H), 6.74 (m, 1 H), 4.78 (t, 1 H, J = 6.4 Hz), 4.62 (s, 1 H), 3.46 (m, 2 H), 2.45-2.17 (m, 4 H), 1.56-1.26 (m, 12 H) ppm. ^¹³C NMR (75 MHz, CDCl₃): δ = 158.2, 152.6, 129.4, 126.4, 125.7, 121.5, 109.5, 66.8, 61.9, 49.2, 35.3, 32.0, 29.8, 25.3, 20.1 ppm. MS (EI): m/z (%) = 287 [M⁺], 214, 202. HRMS: m/z calcd for C₁₈H₂₅O₂N: 287.1872; found: 287.1875.
2-Methyl-1-(3-morpholin-4-yl-3 H -benzofuran-2-ylidene)propan-2-ol (Table 2, Entry 6)
IR (neat): 3419 (br), 2967, 1612, 1462, 1374, 1232, 1115 cm^-¹. ^¹H NMR (400 MHz; CDCl₃): δ = 7.41 (m, 1 H), 7.26 (m, 1 H), 7.01 (m, 1 H), 6.94 (m, 1 H), 5.15 (s, 1 H), 4.79 (s, 1 H), 3.66 (m, 4 H), 2.63 (m, 2 H), 2.41 (m, 2 H), 1.50 (s, 3 H), 1.48 (s, 3 H) ppm. ^¹³C NMR (75 MHz CDCl₃): δ = 157.7, 151.4, 136.1, 129.9, 126.3, 122.4, 114.5, 110.1, 70.6, 67.4, 48.6, 30.8, 30.8 ppm. MS (EI): m/z (%) = 275 [M⁺], 216, 189, 131, 86. HRMS: m/z calcd for C₁₆H₂₁O₃N: 275.1521; found: 275.1519.
2-Methyl-1-(3-pyrrolidin-1-yl-3 H -benzofuran-2-ylidene)propan-2-ol (Table 2, Entry 7)
IR (neat): 3430 (br), 2911, 1672, 1561, 1341, 1160 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 7.35 (m, 1 H), 7.19 (m, 1 H), 6.93 (m, 1 H), 6.87 (m, 1 H), 5.12 (s, 1 H), 4.74 (s, 1 H), 2.57 (m, 2 H), 2.36 (m, 2 H), 1.54-1.24 (m, 10 H) ppm. ^¹³C NMR (75 MHz, CDCl₃): δ = 157.6, 152.2, 129.5, 125.4, 122.2, 113.7, 109.9, 70.6, 67.8, 49.6, 30.9, 26.5, 24.6 ppm. MS (EI): m/z (%) = 258 [M⁺], 189, 131. HRMS: m/z calcd for C₁₆H₂₁O₂N: 258.1494; found: 258.1491.
2-Methyl-1-{3-piperidin-1-yl-3 H -naphtho[2,3- b ]furan-2-ylidene}propan-2-ol (Table 2, Entry 8)
IR (neat): 3581 (br), 2934, 1688, 1522, 1249, 1161 cm^-¹. ^¹H NMR (400 MHz CDCl₃): δ = 8.18 (m, 1 H), 7.83 (m, 1 H), 7.75 (m, 1 H), 7.52 (m, 1 H), 7.38 (m, 1 H), 2.53 (m, 4 H), 1.64-1.32 (m, 12 H) ppm. ^¹³C NMR (75 MHz, CDCl₃): δ = 155.2, 151.2, 131.2, 130.8, 130.5, 128.8, 127.9, 124.0, 124.0, 117.9, 115.1, 111.4, 70.9, 68.2, 49.3, 31.2, 31.1, 26.8, 25.0 ppm. MS (EI): m/z (%) = 323 [M⁺], 264, 181. HRMS: m/z calcd for C₂₁H₂₅O₂N: 323.1885; found: 323.1879.
1-(5-Chloro-3-piperidin-1-yl-3 H -benzofuran-2-ylidene)-2-methylpropan-2-ol (Table 2, Entry 9)
IR (neat): 3401 (br), 2936, 1702, 1608, 1469, 1234, 1154 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 7.34 (s, 1 H), 7.20 (m, 1 H), 6.86 (m, 1 H), 5.14 (m, 1 H), 4.76 (s, 1 H), 2.58 (m, 2 H), 2.39 (m, 2 H), 1.54-1.46 (m, 12 H) ppm. ^¹³C NMR (75 MHz, CDCl₃): δ = 156.2, 152.1, 129.5, 127.4, 126.3, 114.2, 110.9, 70.6, 69.8, 67.8, 49.6, 30.9, 26.5, 24.5 ppm. MS (EI): m/z (%) = 307 [M⁺], 248, 223. HRMS: m/z calcd for C₁₇H₂₂O₂N^³5Cl: 307.1339; found: 307.1344. HRMS: m/z calcd for C₁₇H₂₂O₂N^³7Cl: 309.1312; found: 309.1312.
1-(6-Methoxy-3-piperidin-1-yl-3 H -benzofuran-2-ylidene)-2-methylpropan-2-ol (Table 2, Entry 10)
IR (neat): 3580 (br), 2938, 1736, 1699, 1620, 1444, 1280 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 7.22 (m, 1 H), 6.50 (m, 1 H), 5.09 (m, 1 H), 4.67 (s, 1 H), 3.75 (s, 3 H), 2.53 (m, 2 H), 2.31 (m, 2 H), 1.49-1.36 (m, 12 H) ppm. ^¹³C NMR (75 MHz, CDCl₃): δ = 161.2, 158.9, 153.0, 126.5, 117.2, 113.8, 108.1, 96.1, 70.6, 67.4, 55.7, 49.4, 30.9, 30.8, 26.4, 24.6 ppm. MS (EI): m/z (%) = 303 [M⁺], 244, 219. HRMS: m/z calcd for C₁₈H₂₅O₃N: 303.1834; found: 303.1831.
2-(4,4-Dimethyl-1-piperidin-1-yl-pent-2-ynyl)phenol (1b)
IR (neat): 2936, 2233, 1644, 1465, 1458, 1362, 1244, 1153 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 7.51 (m, 1 H), 7.22 (m, 1 H), 6.87 (m, 2 H), 4.88 (s, 1 H), 2.64 (m, 4 H), 1.68 (m, 6 H), 1.39 (s, 9 H) ppm. ^¹³C NMR (75 MHz, CDCl₃): δ = 158.0, 129.3, 128.6, 122.1, 110.0, 116.4, 99.1, 95.41, 71.3, 60.7, 31.6, 28.0, 26.2, 24.4 ppm. MS (EI): m/z (%) = 271 [M⁺], 186, 84. HRMS: m/z calcd for C₁₈H₂₅ON: 271.1936; found: 271.1933.